Type of Document	Master's Thesis
Author	Falwell, Elizabeth Paige
Author's Email Address	efalwell@vt.edu
URN	etd-06152005-135205
Title	Fibrosarcoma-induced Dysregulation of Interleukin (IL)-1β and IL-18 Activities and their Modulation by Paclitaxel
Degree	Master of Science
Department	Biology
Advisory Committee	Advisor Name Title Elgert, Klaus D. Committee Chair Burger, Carol J. Committee Member Gogal, Robert M. Jr. Committee Member
Keywords	paclitaxel IL-12 fibrosarcoma IL-1β NF-κB nitric oxide IL-18
Date of Defense	2005-06-07
Availability	unrestricted
Abstract Cancer remains an elusive killer due, in part, to the suppression of normal immunologic antitumor responses. Normal host (NH) macrophage (Mφ) populations have tumoricidal effects such as tumor antigen phagocytosis and presentation, and cytokine production. Tumor-infiltrating Mfs may evade these activities by dysregulating production of immunostimulatory cytokines (including Interleukin [IL]-1β, IL-18, and tumor necrosis factor-α [TNF-α]), by production of antagonistic factors. The restoration of IL-1β, IL-18, and TNF-α production by Mφs could re-establish antitumor host immune responses. Previous work in our laboratory suggests that tumor distal (TD) Mφs produce more IL-1β than NH Mφs when stimulated with IFN-γ and lipopolysaccharide (LPS). We hypothesize that the presence of immunomodulatory factors like IL-10 and TGF-β dysregulate IL-1β production in tumor proximal (TP) Mφs. Indeed, IL-1β production was downregulated among in situ TP Mφs. We have proposed that IL-18, a structural homologue to IL-1β was similarly dysregulated in TD and TP Mφs. IL-18 was enhanced in both distal and proximal Mφs. Differences in the functions of these cytokines could account for this dissimilarity. TNF-α, another proinflammatory cytokine, followed the dysregulation pattern of IL-1β in our tumor-burdened hosts (TBH), likely because of the similar functions of these cytokines. Because it is a potential vehicle for immunotherapeutic treatment, paclitaxel’s action on the immune response (TAXOL™) was investigated. Paclitaxel is a potent Mφ activator that upregulates a variety of cytokines in an LPS-like manner. Paclitaxel enhanced TD Mφ production of IL-1β, IL-18, and TNF-α in an LPS-like manner. Production of IL-1β and TNF-α was reduced in TP Mφs when treated with paclitaxel; however, IL-18 production was enhanced. This difference could be due to the different functions of IL-1β and IL-18. To determine whether production of these cytokines translates into downstream expression of transcription products, IL-12 and nitric oxide (NO) were assayed. NO was enhanced distally, but paclitaxel treatment failed to enhance NO production. When treated with paclitaxel, IL-12 was produced by NH and TD Mφs. Collectively, these studies suggest that tumor-induced cytokine imbalances compromise antitumor immunity and paclitaxel may reverse this activity.
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